Amplifying Anti‐Tumor Immune Responses via Mitochondria‐Targeting Near‐Infrared Photodynamic Therapy

Abstract Pro‐inflammatory photodynamic therapy (PDT) holds immense potential to ignite robust and long‐lasting systemic anti‐tumor immune responses. However, the limited penetration depth of conventional ultra violet (UV)‐visible irradiation and the tumor hypoxia microenvironment significantly constrain the efficacy of immune‐regulatory PDT. Here, a mitochondria‐targeting enhanced nanoplatform (NZ @TG ) is reported, activated by near‐infrared (NIR) light‐driven PDT, to address these challenges and amplify systemic anti‐tumor immunity. This nanoplatform employs an interfacial lanthanide‐organic triplet photosensation mechanism to realize localized oxidative damage of oxygen‐rich mitochondria under NIR irradiation. Simultaneously, the exacerbated hypoxia induced by PDT activates a TH302 prodrug, resulting in cell cycle arrest in highly proliferative tumor cells. These combined effects trigger immunogenic cell death (ICD), releasing damage‐associated molecular patterns (DAMPs) to activate immune responses. This approach demonstrates significantly enhanced tumor ablation in deep‐seated lesions in orthotopic liver tumor models and induces long‐term anti‐tumor immune memory. Moreover, the NIR‐PDT‐induced immune activation markedly improves the immune checkpoint blockade (ICB) therapy efficacy. This strategy offers a robust modality for immune activation in cancer therapy, paving the way for effective treatment of deep‐seated tumors and preventing recurrence.